Treatment of visceral pain, E.G., irritable bowel syndrome with nerve-acting agents

ABSTRACT

Methods are provided for use in treating humans suffering from irritable bowel syndrome. In the subject methods, an effective amount of a nerve-acting agent, e.g., lidocaine, topiramate, mexiletine and gabapentin, etc., is administered to a human suffering from irritable bowel syndrome. Also provided are pharmaceutical compositions and kits for use in practicing the subject methods.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] Pursuant to 35 U.S.C. § 119 (e), this application claims priorityto the filing date of the U.S. Provisional Patent Application Serial No.60/338,093 filed Nov. 8, 2001, the disclosure of which is hereinincorporated by reference.

INTRODUCTION

[0002] 1. Field of the Invention

[0003] The field of this invention is visceral pain, i.e., IrritableBowel Syndrome, and the treatment thereof.

[0004] 2. Background of the Invention

[0005] Visceral pain affects the viscera, such as the intestines. Onecommon type of visceral pain is Irritable Bowel Syndrome (IBS). IBS is afunctional bowel disorder in which abdominal pain is associated withdefecation or a change in bowel habits. IBS has elements of anintestinal motility disorder, a visceral sensation disorder, and acentral nervous disorder. While the symptoms of IBS have a physiologicalbasis, no clear mechanism unique to IBS has been identified. Rather, thesame mechanisms that cause occasional abdominal discomfort in healthyindividuals seem to operate to produce the symptoms of IBS. The symptomsof IBS are therefore a product of quantitative differences in the motorreactivity of the intestinal tract, and increased sensitivity to stimulior spontaneous contractions.

[0006] Due to a lack of a readily identifiable structural or biochemicalabnormality in this syndrome, the medical community has developed aconsensus definition and criteria, known as the Rome criteria, to aid indiagnosis of IBS. According to the Rome criteria, IBS is indicated byabdominal pain or discomfort which is (1) relieved by defection and/or(2) associated with a change in frequency or consistency of stools, plustwo or more of the following: altered stool frequency, altered stoolformation, altered stool passage, passage of mucus, and bloating orfeeling of abdominal distention (Dalton, C. and Drossman, D. A., Am FamPhysician 1997 55(3):875-880). Thus, a hallmark of IBS is abdominal painthat is relieved by defecation, and which is associated with a change inthe consistency or frequency of stools. IBS may be diarrhea-predominant,constipation-predominant, or an alternating combination of both.

[0007] Persons with IBS exhibit hypersensitivity, particularlyhyperalgesia (increased response to a painful stimulus), in response topainful distensions in the small bowel and colon and to normalintestinal function. Furthermore, there are also increased or unusualareas of visceral pain. The abdominal pain is often poorly localized,and may be migratory and/or variable in nature. The pain may be worsenedby meals and reduced upon defecation. Furthermore, IBS symptoms,including hyperalgesia, are commonly initiated or exacerbated by stress(Dalton, C. and Drossman, D. A., Am Fam Physician 1997 55(3):875-880).

[0008] IBS is estimated to affect up to 20% of the adult populationworldwide. Women apparently are more often affected than men, and theprevalence of Irritable Bowel Syndrome is lower among the elderly(Camilleri, M. and Choi, M.-G., Aliment Pharmacol Ther 1997-11(1):3-15).It also seems clear that psychological factors, either stress or overtpsychological disease, modulate and exacerbate the physiologicalmechanisms that operate in IBS (Drossman, D. A. et al., Gastroenterology1988 95:701-708).

[0009] Some studies suggest that only about 10% to 50% of thoseafflicted with IBS actually seek medical attention. Nonetheless, IBSstill accounts for up to about 3.5 million physician visits per year,and is the most common diagnosis in a gastroenterologists' practice,accounting for about 25% of all patients (Camilleri and Choi, 1997). Ina study published in 1993, persons afflicted with IBS were found to havemore frequent doctor visits, a lower quality of life, and to miss threetimes as many days from work as those with no bowel symptoms (Drossman,D. A., Dig Dis Sci 1993 38:1569-1580). As a consequence, persons withIBS incur higher health care costs than those without IBS (Talley, N. J.et al., Gastroenterology 1995 109:1736-1741).

[0010] Attempts to treat IBS generally focus on either (1) treatmentsdirected to the intestinal tract (so-called “end organ therapy”) or (2)treatments directed to affective disorders mediated by the CNS which areassociated with IBS (Farthing, M. J. G., Drugs 1998 56(1):11-21). Amongthe former are gut transit accelerants, such as wheat bran, solublefiber, and polycarbophil calcium, for constipation-predominant IBS;antidiarrheals, such as loperamide, diphenoxylate, and codeinephosphate, for diarrhea-predominant IBS; and anticholinergics and smoothmuscle relaxants, such as cimetropium bromide, pinaverium bromide,octilium bromide, trimebutine, and mebeverine, for diarrhea-predominantIBS and abdominal pain. In addition, alterations in diet have beentargeted for those patients with food sensitivities or food allergies.

[0011] The end organ therapy treatments for IBS have proved minimallyeffective or contain inherent drawbacks that limit their usefulness. Forexample, while the gut accelerants are useful to accelerate gut transit,they also exacerbate abdominal pain and bloating. Likewise, whileantidiarrheals, such as loperamide, are often effective in treatingdiarrhea-predominant IBS, they are ineffective in treating theadditional symptoms associated with IBS, such as abdominal pain. As aconsequence, end organ therapy often is limited to patients with mild ormoderate symptoms.

[0012] The anticholinergics and smooth muscle relaxants are effective inrelieving pain associated with IBS, although their effects on othersymptoms associated with IBS is unclear (Committee, Gastroenterology1997 112:2120-2137; Pace, F. et al., Digestion 1995 56:433-442). Inaddition, some of the most effective compounds in these classes are notavailable for use in the United States, since they have not beenapproved by the Federal Food and Drug Administration (Committee, 1997).Finally, dietary alterations are of limited utility for a small segmentof IBS patients.

[0013] Central nervous system treatments have received attention aspotential IBS therapies. The tricyclic antidepressants, such asamitriptyline, imipramine, and doxepin, are frequently used to treatIBS, due to the neuromodulatory and analgesic properties of thesecompounds, which are independent of their psychotropic effects. However,because of their psychotropic properties, administration of these drugsrequires long-term care, and is usually only given to patients withsevere or refractory symptoms, impaired daily function, or associateddepression or anxiety attacks. Furthermore, the newer antidepressants,in particular serotonin (5HT3) reuptake inhibitors, such as fluoxetine,sertraline, and paroxetine, have not been shown to be more effectivethan the tricyclic antidepressants (Committee, 1997). Conversely, 5HT3inhibitors are used for relief of diarrhea prone IBS. Unfortunately,significant morbidity and mortality has been reported.

[0014] There remains continued interest in identifying new methods fortreating IBS.

[0015] Relevant Literature

[0016] U.S. Patents of interest include: U.S. Pat. Nos. 6,284,770;6,228,040; 6,203,797; 6,194,382; 5,965,557; 5,900,233; 5840,332;6,127,418; and 6,297,226.

SUMMARY OF THE INVENTION

[0017] Methods are provided for use in treating humans suffering fromvisceral pain, e.g., irritable bowel syndrome. In the subject methods,an effective amount of a nerve-acting agent, e.g., lidocaine,topiramate, mexiletine or gabapentin, is administered to a humansuffering from irritable bowel syndrome. Also provided arepharmaceutical compositions and kits for use in practicing the subjectmethods.

FEATURES OF THE INVENTION

[0018] The subject invention provides method of treating a human withIrritable Bowel Syndrome by administering to said human an effectiveamount of a nerve-acting agent. In certain embodiments, the nerve-actingagent is an agent that attenuates visceral nerve signals. In certainembodiments, the nerve-acting agent is a frequency dependant sodiumchannel blocker (e.g., lidocaine, topiramate and mexiletine, etc.). Incertain embodiments, the nerve-acting agent is selected from the groupof agents known in the art as anti-convulsant agents. In certainembodiments, the nerve-acting agent is gabapentin or an analog thereof.In certain embodiments, the nerve-acting agent is administeredsystemically. In certain embodiments, the nerve-acting agent isadministered orally. In certain embodiments, the nerve-acting agent isadministered intravenously, transdermally, topically, or by intraspinal,intrathecal, epidural, intracerebral, intraventricular, inhalational,per-rectal, intravaginal, nasal, buccal, intramuscular intradermal,intra-peritoneal, per-NGT, intra-arterial, or sublingual means.

[0019] Typically, the nerve-acting agent is administered as apharmaceutical preparation. In certain embodiments, the method furtherincludes administering an effective amount of a non-nerve-actingIrritable Bowel Syndrome agent.

[0020] Also provided are kits for use in treating a human for IrritableBowel Syndrome according to the subject methods, where the kits includean effective amount of a nerve-acting agent; and instructions for use intreating a human for Irritable Bowel Syndrome by administration of saidnerve-acting agent. In certain embodiments, the kits also include aneffective amount of a non-nerve-acting Irritable Bowel Syndrome agent,which agent may be present in a pharmaceutical composition that alsoincludes the nerve-acting agent.

[0021] Also provided are pharmaceutical preparations that include anerve-acting agent in an oral amount ranging from about 0.001 to about10,000 (mcg, mg, gm, %, mg/dl, mcg/ml, international units (IU), ml/hr,mcg/hr, mg/kg/hr, mg/kg/min, mcg/kg/hr, mcg/kg/min, picograms,nanograms, or milliequivalants) present in a pharmaceutically acceptablevehicle, where such compositions are specifically tailored for use inthe subject methods, and may include an additional non-nerve-acting IBStreatment agent.

BRIEF DESCRIPTION OF THE FIGURES

[0022] FIGS. 1 to 8 provide graphical results of various experimentsreported in the experimental section below.

DESCRIPTION OF THE SPECIFIC EMBODIMENTS

[0023] Methods are provided for use in treating humans suffering fromIrritable Bowel Syndrome. In the subject methods, an effective amount ofa nerve-acting agent, e.g., lidocaine, topiramate, mexiletine andgabapentin, etc., is administered to a human suffering from IrritableBowel Syndrome. Also provided are pharmaceutical compositions and kitsfor use in practicing the subject methods.

[0024] Before the subject invention is described further, it is to beunderstood that the invention is not limited to the particularembodiments of the invention described below, as variations of theparticular embodiments may be made and still fall within the scope ofthe appended claims. It is also to be understood that the terminologyemployed is for the purpose of describing particular embodiments, and isnot intended to be limiting. Instead, the scope of the present inventionwill be established by the appended claims.

[0025] In this specification and the appended claims, the singular forms“a,” “an” and “the” include plural reference unless the context clearlydictates otherwise. Unless defined otherwise, all technical andscientific terms used herein have the same meaning as commonlyunderstood to one of ordinary skill in the art to which this inventionbelongs.

[0026] Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimit of that range, and any other stated or intervening value in thatstated range, is encompassed within the invention. The upper and lowerlimits of these smaller ranges may independently be included in thesmaller ranges, and are also encompassed within the invention, subjectto any specifically excluded limit in the stated range. Where the statedrange includes one or both of the limits, ranges excluding either orboth of those included limits are also included in the invention.

[0027] Unless defined otherwise, all technical and scientific terms usedherein have the same meaning as commonly understood to one of ordinaryskill in the art to which this invention belongs. Although any methods,devices and materials similar or equivalent to those described hereincan be used in the practice or testing of the invention, the preferredmethods, devices and materials are now described.

[0028] All publications mentioned herein are incorporated herein byreference for the purpose of describing and disclosing the componentswhich are described in the publications which might be used inconnection with the presently described invention.

[0029] As summarized above, the subject invention provides methods oftreating a human subject suffering from Irritable Bowel Syndrome, aswell as pharmaceutical preparations and kits for use in practicing thesubject methods. Each of these components is now described in greaterdetail below.

[0030] This invention pertains to the discovery that nerve-acting agentsare effective for ameliorating or treating Irritable Bowel Syndrome in ahuman. Irritable Bowel Syndrome or “IBS” is defined above. The humanpatient, subject or host that is treated with the subject methods may bemale or female, and may be any age, e.g., a child or adult. The term“ameliorating” or “ameliorate” refers to any indicia of success in thetreatment of a pathology or condition, including any objective orsubjective parameter such as abatement, remission or diminishing ofsymptoms or an improvement in a patient's physical or mental well-being.Amelioration of symptoms can be based on objective or subjectiveparameters; including the results of a physical examination and/or apsychiatric evaluation. By “treatment” is meant at least an ameliorationof at least one of the symptoms associated with the disease conditionafflicting the host, where amelioration is used in a broad sense torefer to at least a reduction in the magnitude of a parameter, e.g.symptom, associated with the pathological condition being treated, suchas bloating and pain associated therewith. As such, treatment alsoincludes situations where the pathological condition, or at leastsymptoms associated therewith, are completely inhibited, e.g. preventedfrom happening, or stopped, e.g. terminated, such that the host nolonger suffers from the pathological condition, or at least the symptomsthat characterize the pathological condition.

[0031] In practicing the subject methods, an effective amount of anerve-acting agent is administered to a human subject diagnosed orsuspected of having IBS. The subject may be diagnosed to have IBS usingany convenient protocol, including the diagnostic protocols described inU.S. Pat. Nos. 6,284,770; 6,228,040; 6,203,797; 6,194,382; 5,965,557;5,900,233; the disclosures of which are herein incorporated byreference.

[0032] Nerve-acting agents of interest that find use in the subjectmethods are, in many embodiments, agents that attenuate visceral nervesignals and/or decrease neuronal activity when administered to thesubject. Representative agents of interest include, but are not limitedto: local anesthetics; anticonvulsants; and the like. Local anestheticagents of interest include, but are not limited to: lidocaine,ropivicaine, bupivicaine, butamben, butanilicaine, ethyl aminobenzoate,fornocaine, hydroxyprocaine, isobutyl p-aminobenzoate, naepaine,octacaine, parethoxycaine, piridocaine, prilocaine, procaine, risocaine,tolycaine, trimecaine, ethylaminobenzoate (benzocaine), etc. Also ofinterest are anticonvulsants. Anticonvulsants of interest include, butare not limited to: lamotrigine, gabapentin, valproic acid, topiramate,famotodine, phenobarbital, diphenylhydantoin, phenytoin, mephenytoin,ethotoin, mephobarbital, primidone, carbamazepine, ethosuximide,methsuximide, phensuximide, trimethadione, benzodiazepine, phenacemide,acetazolamide, progabide, clonazepam, divalproex sodium, magnesiumsulfate injection, metharbital, paramethadione, phenytoin sodium,valproate sodium, clobazam, sulthiame, dilantin, diphenylan andL-5hydroxytryptophan.. In certain embodiments, sodium channel blockersare of interest, e.g., lidocaine, topiramate, and mexiletine, where theagent is not gabapentin or an analog thereof. In other embodiments, theagent is gapapentin or an analog thereof, e.g.,1-aminomethyl-3-methylcyclohexyl)acetic acid,(1-aminomethyl-3-methylcyclopentyl)acetic acid, and(1-aminomethyl-3,4-dimethylcyclopentyl)acetic acid, etc.

[0033] In the methods of the subject invention, an effective.amount ofthe active agent(s) is administered to the subject, where “effectiveamount” means a dosage sufficient to produce the desired result, e.g.,an improvement in a disease condition or the symptoms associatedtherewith of the IBS condition being treated, e.g., bloating pain, etc.The active agent may be administered to the host using any convenientmeans capable of producing the desired result. Thus, the active agentcan be incorporated into a variety of formulations for therapeuticadministration. More particularly, the active agent of the presentinvention can be formulated into pharmaceutical compositions bycombination with appropriate, pharmaceutically acceptable carriers ordilutents, and may be formulated into preparations in solid, semi-solid,liquid or gaseous forms, such as tablets, capsules, powders, granules,ointments, solutions, suppositories, injections, inhalants and aerosols.As such, administration of the active agent can be achieved in variousways, including oral, buccal, rectal, parenteral, intraperitoneal,intradermal, transdermal, intracheal, etc., administration. Inpharmaceutical dosage forms, the active agent may be administered aloneor in combination with other pharmaceutically active compounds. Thefollowing methods and excipients are merely exemplary and are in no waylimiting.

[0034] For oral preparations, the active agent can be used alone or incombination with appropriate additives to make tablets, powders,granules or capsules (including sustained released formulations), forexample, with conventional additives, such as lactose, mannitol, cornstarch or potato starch; with binders, such as crystalline cellulose,cellulose derivatives, acacia, corn starch or gelatins; withdisintegrators, such as corn starch, potato starch or sodiumcarboxymethylcellulose; with lubricants, such as talc or magnesiumstearate; and if desired, with diluents, buffering agents, moisteningagents, preservatives and flavoring agents.

[0035] The active agent can be formulated into preparations forinjection by dissolving, suspending or emulsifying them in an aqueous ornonaqueous solvent, such as vegetable or other similar oils, syntheticaliphatic acid glycerides, esters of higher aliphatic acids or propyleneglycol; and if desired, with conventional additives such assolubilizers, isotonic agents, suspending agents, emulsifying agents,stabilizers and preservatives.

[0036] The active agent can be utilized in aerosol formulation to beadministered via inhalation. The compounds of the present invention canbe formulated into pressurized acceptable propellants such asdichlorodifluoromethane, propane, nitrogen and the like. Furthermore,the active agent can be made into suppositories by mixing with a varietyof bases such as emulsifying bases or water-soluble bases: The compoundsof the present invention can be administered rectally via a suppositoryThe suppository can include vehicles such as cocoa butter, carbowaxesand polyethylene glycols, which melt at body temperature, yet aresolidified at room temperature.

[0037] Unit dosage forms for oral or rectal administration such assyrups, elixirs, and suspensions may be provided wherein each dosageunit, for example, teaspoonful, tablespoonful, tablet or suppository,contains a predetermined amount of the composition containing activeagent. Similarly, unit dosage forms for injection or intravenousadministration may comprise the active agent in a composition as asolution in sterile water, normal saline or another pharmaceuticallyacceptable carrier.

[0038] The term “unit dosage form,” as used herein, refers to physicallydiscrete units suitable as unitary dosages for human and animalsubjects, each unit containing a predetermined quantity of compounds ofthe present invention calculated in an amount sufficient to produce thedesired effect in association with a pharmaceutically acceptablediluent, carrier or vehicle. The specifications for the novel unitdosage forms of the present invention depend on the particular compoundemployed and the effect to be achieved, and the pharmacodynamicsassociated with each compound in the host.

[0039] The pharmaceutically acceptable excipients, such as vehicles,adjuvants, carriers or diluents, are readily available to the public.Moreover, pharmaceutically acceptable auxiliary substances, such as pHadjusting and buffering agents, tonicity adjusting agents, stabilizers,wetting agents and the like, are readily available to the public.

[0040] Details on techniques for formulation and administration are welldescribed in the scientific and patent literature, see, for example, thelatest edition of “Remington's Pharmaceutical Sciences” (MaackPublishing Co, Easton Pa.).

[0041] Representative specific formulations are provided forrepresentative drugs in the Experimental Section, below.

[0042] The methods of the invention ameliorate IBS, i.e., prevent, slowthe onset of, decrease the frequency of, diminish. the severity of orcure IBS and/or its complications. The amount of, active, agent adequateto accomplish this result is defined as a “therapeutically effectivedose.” The dosage schedule and amounts effective for this use, i.e., the“dosing regimen,” will depend upon a variety of factors, including thestage of the disease or condition, the severity of the disease orcondition, the patient's physical status, age and the like. Incalculating the dosage regimen for a patient, the mode of administrationalso is taken into consideration. The dosage regimen must also take intoconsideration the pharmacokinetics, i.e., the active agent's rate ofabsorption, bioavailability, metabolism, clearance, and the like (see,for example, Hidalgo-Aragones (1996) J. Steroid Biochem. Mol. Biol.58:611-617; Groning (1996) Pharmazie 51:337-341; Fotherby (1996)Contraception 54:59-69; Johnson (1995) J. Pharm. Sci. 84:1144-1146;Rohatagi (1995) Pharmazie 50:610-613; Brophy (1983) Eur. J. Clin.Pharmacol. 24:103-108; the latest Remington's, supra). The state of theart allows the clinician to determine the dosage regimen for eachindividual patient, active agent and disease or condition treated. As anillustrative example, the guidelines provided below for the specificrepresentative active agents of the experimental section can be used asguidance to determine the dosage regiment, i.e., dose schedule anddosage levels, of any active agent administered when practicing themethods of the invention.

[0043] Single or multiple administrations of the active agentformulations may be administered depending on the dosage and frequencyas required and tolerated by the patient. In certain embodiments, theamount of active agent employed in pharmaceutical preparations usefulfor the subject invention range from about 0.001 to about 10,000 mcg. Incertain embodiments, the amount of active agent employed inpharmaceutical preparations useful for the subject invention range fromabout 0.001 to about 10,000 mg. In certain embodiments, the amount ofactive agent employed in pharmaceutical preparations useful for thesubject invention range from about 0.001 to about 10,000 gm. In certainembodiments, the amount of active agent employed in pharmaceuticalpreparations useful for the subject invention range from about 0.001 toabout 10,000%. In certain embodiments, the amount of active agentemployed in pharmaceutical preparations useful for the subject inventionrange from about 0.001 to about 10,000 mg/dl. In certain embodiments,the amount of active agent employed in pharmaceutical preparationsuseful for the subject invention range from about 0.001 to about 10,000mcg/ml. In certain embodiments, the amount of active agent employed inpharmaceutical preparations useful for the subject invention range fromabout 0.001 to about 10,000 international units (IU). In certainembodiments, the amount of active agent employed in pharmaceuticalpreparations useful for the subject invention range from about 0.001 toabout 10,000 ml/hr. In certain embodiments, the amount of active agentemployed in pharmaceutical preparations useful for the subject inventionrange from about 0.001 to about 10,000 mcg/hr. In certain embodiments,the amount of active agent employed in pharmaceutical preparationsuseful for the subject invention range from about 0.001 to about 10,000mg/kg/hr. In certain embodiments, the amount of active agent employed inpharmaceutical preparations useful for the subject invention range fromabout 0.001 to about 10,000 mg/kg/min. In certain embodiments, theamount of active agent employed in pharmaceutical preparations usefulfor the subject invention range from about 0.001 to about 10,000mcg/kg/hr. In certain embodiments, the amount of active agent employedin pharmaceutical preparations useful for the subject invention rangefrom about 0.001 to about 10,000 mcg/kg/min. In certain embodiments, theamount of active agent employed in pharmaceutical preparations usefulfor the subject invention range from about 0.001 to about 10,000picograms. In certain embodiments, the amount of active agent employedin pharmaceutical preparations useful for the subject invention rangefrom about 0.001 to about 10,000 nanograms. In certain embodiments, theamount of active agent employed in pharmaceutical preparations usefulfor the subject invention range from about 0.001 to about 10,000milliequivalants.

[0044] The formulations should provide a sufficient quantity of activeagent to effectively ameliorate the IBS condition. Thus, a typicalpharmaceutical formulation for oral administration of gabapentin wouldbe about 0.5 to about 25.0, often from about 1.0 to 20.0 mg/kg of bodyweight per patient per day, e.g., 1.42 to about 17.14 mg/kg of bodyweight per patient per day. Oral mexiletine doses range from 0.5 toabout 25.0, often from about 1.0 to 15.0 mg/kg of body weight perpatient per day, e.g., 1.14 to 12.85 mg/kg. Oral topiramate dosagesrange from 0.1 to about 10.0, often from about 0.2 to 5.0 mg/kg of bodyweight per patient per day, e.g., 0.35 to 2.85 mg/kg. Lower dosages ofthese agents may be used, particularly when the drug is administered toan anatomically secluded site, such as .the cerebral spinal fluid (CSF).space, in contrast to administration orally, into the blood stream, intoa body cavity or into a lumen of an organ. Substantially higher dosagesare possible in topical administration. Actual methods for preparingparenterally administrable active agent formulations will be known orapparent to those skilled in the art and are described in more detail insuch publications as Remington's Pharmaceutical Science, 15th ed., MaackPublishing Company, Easton, Pa. (1980). In a preferred embodiment of theinvention, the invention provides for a method of treating IBS byadministering active agent in a daily amount of about 0.1 to 25.0 mg/kg,e.g., from about 0.35 to about 17.14 mg per kilogram of body weight perday. Using this dosage, the administration can continue for a period ofabout 30 to 90 days.

[0045] After a pharmaceutical comprising an active agent of theinvention has been formulated in an acceptable carrier, it can be placedin an appropriate container and labeled for treatment of an indicatedcondition. For administration of active agents, such labeling wouldinclude, for example, instructions concerning the amount, frequency andmethod of administration. In one embodiment, the invention provides fora kit for the amelioration of psychosis in a human, which includes anactive agent and instructional material teaching the indications, dosageand schedule of administration of the active agent.

[0046] In certain embodiments, the methods further includedadministration of an effective amount of a non-nerve-acting agent whichalso imparts relief from IBS or symptoms thereof, where such agentsinclude: wheat bran, soluble fiber, and polycarbophil calcium, forconstipation-predominant IBS; antidiarrheals, such as loperamide,diphenoxylate, and codeine phosphate, for diarrhea-predominant IBS; andanticholinergics and smooth muscle relaxants, such as cimetropiumbromide, pinaverium bromide, octilium bromide, trimebutine, andmebeverine, for diarrhea-predominant IBS and abdominal pain; tricyclicantidepressants, such as amitriptyline, imipramine, and doxepin;specific serotonin reuptake inhibitors, such as fluoxetine, serraline,and paroxetine; and the like.

[0047] Such agents may be administered as a separate composition or inthe same composition as the nerve-acting agent as described above.

[0048] As indicated above, the subject invention provides for at leastamelioration of IBS symptoms. For example, in certain embodiments, thesubject invention provides for a reduction in visceral pain of at leastabout 50%; usually at least about 33% and more usually at least about25%, as measured using the assay, described in the experimental section,below. Likewise, in certain embodiments the subject invention providesfor a reduction in bloating of at least about 50%, usually at leastabout 33% and more usually at least about 25%, as determined using theassay described in the experimental section, below.

[0049] Kits with unit doses of the active agent(s), usually in oral orinjectable doses and often in a storage stable formulation, areprovided. Preferred compounds and unit doses are those described hereinabove. In such kits, in addition to the containers containing the unitdoses will be an informational package insert describing the useagent(s) in treating IBS. These instructions may be present in thesubject kits in a variety of forms, one or more of which may be presentin the kit. One form in which these instructions may be present is asprinted information on a suitable medium or substrate, e.g., a piece orpieces of paper on which the information is printed, in the packaging ofthe kit, in a package insert, etc. Yet another means would be a computerreadable medium, e.g., diskette, CD, etc., on which the information hasbeen recorded. Yet another means that may be present is a websiteaddress which may be used via the Internet to access the information ata removed site. Any convenient means may be present in the kits.

[0050] The following examples are offered by way of illustration, andnot by way of limitation.

EXPERIMENTAL

[0051] I. Introduction

[0052] This study assesses the use of nerve-acting drugs for thetreatment of visceral pain, such as Irritable Bowel Syndrome (IBS).Common symptoms in lBS, such as diarrhea, constipation or abdominal painand bloating are not currently well explained by any structural orbiochemical abnormality. Drugs selected for this study, i.e. lidocaine,mexiletine and topiramate, all have some degree of sodium channelblocking activity. Gabapentin (Neurontin) has a less defined mechanismin decreasing irritable nerve signals. Possible mechanisms includeselective depression of spinal cord pain transmission and reducingdischarge of tonically active peripheral nerve fibers.

[0053] II. Methods

[0054] This is a longitudinal single blinded, randomized placebocontrolled study in which patients act as their own controls. Subjectswere volunteers who met the Rome Criteria for IBS and without otheractive bowel disease (i.e. GERD, colon cancer). Both adult men and womenparticipated, ranging in age from 23 to 75 years old, with greaternumber of women by a ratio of 2.5:1. Subjects responded to a BowelSymptom Questionnaire (B. Naliboff, UCLA) as well as a Brief Mood Survey(D. Burns, Stanford). Baseline questionnaire results were taken justprior to any drug treatment as well as shortly after. In addition, datawas collected during a washout period of one week without any studydrug. Drugs studied included intravenous lidocaine and a trial of theoral mexiletine, topiramate, gabapentin or placebo.

[0055] A titration period of three to four weeks is being used tostabilize each patient on an efficacious dose of medication. Oralmexiletine (daily dose 300 to 900 mg), topiramate (daily dose 15 to 100mg) and gabapentin (daily dose of 300 to 900 mg per day) and a placebowere taken in syrup that was blinded to the patient. During each week ofthe titration period, the cocktail was modified to allow a gradualincrease or decrease in dose. Results were collected weekly byquestionnaires.

[0056] Benefit in treating chronic IBS using nerve-acting agents wasquantified by a decrease in mean values of abdominal pain with a20-point Visual Analogue scale and a decrease in bowel symptoms(bloating, etc.) using a 20-point scale. Mood was also followed by aBrief Mood Survey, which rates Depression, Anxiety, Panic, Anger andSuicidal Urge (88 points maximum total).

[0057] III. Results

[0058] The impact of intravenous lidocaine on abdominal pain andbloating appeared significant in 22 subjects thus far. All patients hada significant drop in their scores. VAS Pain scores (20 point scale)showed a mean reduction of 4.80 and a p-value of 0.000 (FIG. 1).Bloating showed a mean reduction of 6.8 and a p-value of 0.000 (FIG. 2).Results from the oral drugs revealed a general decrease in mean VASabdominal and bloating (20 point) scores, although less significant(FIGS. 3 & 4).

[0059] For gabapentin (Neurontin) there was a drop in mean VAS painscores with a p-value of increasing significance as dosage increasedfrom 300 to 600 to 900 mg (p=0.06, 0.04 & 0. 01) (FIG. 5). Mexiletinealso showed significant results in decreasing bloating, in fact, at alldosages 300 mg, 450 mg & 900 mg ; p=0.02, 0.04 & 0.01)(FIG. 6). Ofparticular interest, the placebo did not seem to reduce VAS pain orbloating significantly (FIGS. 7& 8) compared to all study drugs. Sideeffects reported were sedation and tongue numbness, which resolved afterdrug was discontinued. Two subjects reported fatigue on topiramate 25 mgqhs, which also resolved after discontinuation. In further analysis,where Ho (Null Hypothesis) is no reduction of symptom versus H1, whichis some reduction, the following was noted:

[0060] Placebo does not seem to reduce VAS or bloating significantly,but it does influence the mood, through placebo effect.

[0061] Lidocaine is the most influential drug of all, highly significantfor VAS, bloating and mood.

[0062] Effects of gabapentin become more pronounced as the dosage isincreased.

[0063] Effects of mexiletine are significant at all dosages.

[0064] Topiramate has the least effect of all drugs. The effects barelybecome significant at doses of 50 mg and higher.

[0065] Test for the difference in sexes was not significant.

[0066] In assessing whether Ho means the drug effect is equal to placeboeffect and H1 is where drug has more effect than placebo, the followingwas noted:

[0067] All the drugs have similar effect on the mood as placebo anddiffer from it (for mood) only at highest doses.

[0068] Lidocaine has much stronger effect than placebo.

[0069] Gabapentin is different from placebo at doses 600 mg and higher.

[0070] Mexiletine is different from placebo at all levels for VAS andbloating.

[0071] Topiramate is different from placebo for VAS and bloating atdoses 50 mg and higher.

[0072] In addition, regression analysis to determine if the scoredepends on drug dosage. The following findings were made:

[0073] Larger doses of gabapentin & mexiletine have some effect on VAS &bloating. This is especially true for mexiletine. Both are not veryimportant for mood.

[0074] Larger doses of topiramate do not significantly reduce any scorein a predictable manner, although 60 mg showed a borderline effect ondecreasing bloating.

[0075] IV. Conclusion

[0076] Intravenous lidocaine appears to be very effective in immediatelyrelieving symptoms of abdominal pain, bloating and distension in IBS.The data indicated that lidocaine and oral nerve-acting drugs arebeneficial treatments for relief of visceral pain and symptoms as seenin Irritable Bowel Syndrome. Their effect may relate to attenuation ofexcess activity of visceral nerves as well as brain-gut pathways, evenat low therapeutic doses. Oral nerve-acting agents also play a role inimproving improve pain, bowel symptoms & mood at lower therapeuticdosages. The novel use of such drugs has potential for futurepharmaceutical design.

[0077] It is evident from the above discussion and results that thesubject invention provides an effective new way of treating irritablebowel syndrome. As such, the subject invention represents a significantcontribution to the art.

[0078] All publications and patent applications cited in thisspecification are herein incorporated by reference as if each individualpublication or patent application were specifically and individuallyindicated to be incorporated by reference. The citation of anypublication is for its disclosure prior to the filing date and shouldnot be construed as an admission that the present invention is notentitled to antedate such publication by virtue of prior invention.

[0079] Although the foregoing invention has been described in somedetail by way of illustration and example for purposes of clarity ofunderstanding, it is readily apparent to those of ordinary skill in theart in light of the teachings of this invention that certain changes andmodifications may be made thereto without departing from the spirit orscope of the appended claims.

What is claimed is:
 1. A method of treating a human with Irritable BowelSyndrome, said method comprising: administering to said human aneffective amount of a nerve-acting agent.
 2. The method according toclaim 1, wherein said nerve-acting agent is an agent that attenuatesvisceral nerve signals.
 3. The method according to claim 2, wherein saidnerve-acting agent is a frequency dependant sodium channel blocker. 4.The method according to claim 2, wherein said nerve-acting agent is ananti-convulsant agent.
 5. The method according to claim 2, wherein saidnerve-acting agent is chosen from gabapentin, lidocaine, topiraimate andmexiletine or analogs thereof.
 6. The method according to claim 5,wherein said agent is gabapentin, lidocaine, topiramate or mexiletine.7. The method according to claim 1, wherein said nerve-acting agent isadministered intravenously.
 8. The method according to claim 7, whereinsaid nerve-acting agent is administered orally.
 9. The method accordingto claim 7, wherein said nerve-acting agent is administeredtransdermally.
 10. The method according to claim 1, wherein saidnerve-acting agent is administered topically, intraspinally,intrathecally, epidurally, intra-cerebrally, intraventricularly,inhalationally, per-rectally, intravaginally, nasally, buccally,intramuscularly, intradermally, intra-peritoneally, per-NGT,intra-arterially, or sublingually
 11. The method according to claim 1,wherein said nerve-acting agent is administered as a pharmaceuticalpreparation.
 12. The method according to claim 1, wherein said methodfurther comprises administering an effective amount of anon-nerve-acting irritable bowel syndrome agent.
 13. A kit for use intreating a human for irritable bowel syndrome, said kit comprising: (a)an effective amount of a nerve-acting agent; and (b) instructions foruse in treating a human for irritable bowel syndrome by administrationof said nerve-acting agent.
 14. The kit according to claim 13, whereinsaid nerve-acting agent is an agent that attenuates visceral nervesignals.
 15. The kit according to claim 14, wherein said nerve-actingagent is a frequency dependant sodium channel blocker.
 16. The kitaccording to claim 15, wherein said nerve-acting agent is selected fromthe group consisting of anti-convulsant agents.
 17. The kit according toclaim 14, wherein said nerve-acting agent is gabapentin, lidocaine,topiramate, mexiletine or analogs thereof.
 18. The kit according toclaim 17, wherein said agent is gabapentin, lidocaine, topiramate ormexiletine.
 19. The kit according to claim 13, wherein said instructionsteach to administer said nerve-acting agent systemically.
 20. The kitaccording to claim 19, wherein said instructions teach to administersaid nerve-acting agent orally.
 21. The kit according to claim 19,wherein said instructions teach to administer said nerve-acting agenttransdermally.
 22. The kit according to claim 21, wherein saidinstructions teach to administer said nerve-acting agent subcutaneously,intraspinally, intra-cerebrally, or epidurally.
 23. The kit according toclaim 13, wherein said nerve-acting agent is administered as apharmaceutical preparation.
 24. The kit according to claim 13, whereinsaid kit further comprises an effective amount of a non-nerve-actingirritable bowel syndrome agent:
 25. The kit according to claim 24,wherein said non-nerve-acting irritable bowel syndrome agent is presentin a pharmaceutical composition that also includes said nerve-actingagent.
 26. A pharmaceutical preparation comprising a nerve-acting agentin an amount selected for treatment of Irritable Bowel Syndrome presentin a pharmaceutically acceptable vehicle.
 27. The pharmaceuticalpreparation according to claim 26, wherein said nerve-acting agent is anagent that attenuates visceral nerve signals.
 28. The pharmaceuticalpreparation according to claim 27, wherein said nerve-acting agent is afrequency dependant sodium channel blocker.
 29. The pharmaceuticalpreparation according to claim 26, wherein said nerve-acting agent is ananticonvulsant agents
 30. The pharmaceutical preparation according toclaim 27, wherein said nerve-acting agent is gapapentin, lidocaine,topiramate, mexiletine or analogs thereof.
 31. The pharmaceuticalpreparation according to claim 30, wherein said agent is gabapentin,lidocaine, topiramate or mexiletine.
 32. The pharmaceutical preparationaccording to claim 31, wherein said preparation further comprises aneffective amount of a non-nerve-acting irritable bowel syndrome agent.